Cortical Bone Porosity Identifies Diabetes Subjects With Fragility Fractures

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DESCRIPTION (provided by applicant): Cortical Bone Porosity Identifies Diabetes Subjects With Fragility Fractures Abstract The broad challenge area for this grant application is (03) Biomarker Discovery and Validation. Quantitative imaging techniques have, due to their non-invasive nature, gained substantial significance as biomarkers. This is in particular true for musculoskeletal imaging where imaging biomarkers are developed to better understand bone structure and stability. Thus the specific challenge area 03-AR-102* focuses on developing novel imaging (proteomic, or genomic) approaches to identify the risk for fragility fractures. This project will define and validate novel measures of bone quality that are more predictive than bone mineral density measurements. Bone mineral density (BMD) is currently the best-established bone biomarker to predict fracture risk in osteoporosis. Dual X-ray absorptiometry (DXA) has shown good performance in differentiating subjects with and without fractures, predicting fracture risk and monitoring therapy. However, in certain disease entities limitations of BMD measurements have been acknowledged and among these diabetic bone disease is of outstanding importance. A large number of studies have shown that while fracture risk in subjects with type II diabetes is increased, diabetics also have a higher BMD. This paradox has not been well understood and specific diagnostic techniques to better assess fracture risk in diabetic subjects have not been established. The NIH has previously coined the term "bone quality" to better characterize entities of bone strength which are not well quantified with bone mass or BMD. It is generally accepted that bone quality must play a central role in the increased number of fragility fractures in diabetics and among the measures of bone quality those focusing on cortical and trabecular bone architecture are outstanding. Finding a strong, non-invasive bone quality biomarker to better predict fragility fractures in diabetic patients is clearly a major challenge area, given the increasing socio-economical burden of diabetes and the devastating consequences of fragility fractures in these patients. In a recent intramural research pilot project we were able to study bone structure parameters in diabetic subjects with and without low energy fractures and non-diabetic controls. We obtained BMD measurements using quantitative CT (QCT) and studied cortical and trabecular bone structure with high resolution peripheral QCT (hr-pQCT) and high resolution MRI. Hr-pQCT is a novel imaging modality currently providing the best isotropic spatial resolution (voxel size) to visualize cortical and trabecular bone structure in vivo at the distal tibia and radius. Our research group has acquired extensive experience with this technique, in particular concerning image post-processing to extract structural parameters including cortical porosity and finite element analysis derived surrogate markers of bone strength. We also performed bone marrow MR spectroscopy of the lumbar spine in a subset of these patients to characterize bone marrow fat composition, as this may be of significant importance in understanding pathophysiology of diabetic bone disease. The results of this study showed, that while neither BMD nor trabecular structure parameters were able to differentiate fragility fracture and non-fracture diabetic patient groups, substantial, significant differences in cortical bone porosity and parameters based on finite element analysis were found. Also a trend was found for higher bone marrow fat in diabetic subjects versus normal controls. These findings need to be confirmed by studying larger patient groups, yet could potentially have substantial implications for quantifying risk of fragility fractures in diabetic subjects. In this grant application we propose to study cortical porosity in four subject groups, with and without diabetes and with and without fragility fractures to clinically validate the results found in our pilot study. Our hypothesis is that using hr-pQCT derived measures of cortical bone porosity and finite element analysis as well as MR spectroscopy derived bone marrow fat we will be able to differentiate diabetic subjects with and without fragility fractures. We also hypothesize that diabetic subjects with fragility fractures will have different cortical bone structure compared to non-diabetic subjects with and without fragility fractures and that BMD based parameters will not be able to differentiate diabetics with fractures versus diabetics and controls without fracture. Finding a strong, non-invasive bone quality biomarker to better predict fragility fractures in diabetic patients is clearly a major challenge area, given the increasing socio-economical burden of diabetes and the devastating consequences of fragility fractures in these patients. We believe, based on our preliminary data, that with our novel biomarkers we may be able to better characterize fracture risk in diabetic patients.